The naturally occurring polyamines (PA) are biologically active substances with hormone-like properties which promote cell growth in a variety of plant and animal tissues, and also appear to play an important role in the modulation of neoplastic growth in patients with cancer. Relatively little, however, is known about their role in man under normal and non-neoplastic conditions. Current preliminary studies in this laboratory indicate that PA may have at least two wholly unrecognized and vital roles in influencing the integrity of the artery wall and the possible development of atherosclerosis: 1) as one of the so-called "platelet growth factors" released from the platelets at sites of arterial injury, and 2) as an intracellular mediator or second messenger for a number of hormones (growth hormone, corticosteroids, insulin, and estrogen) and hypoxia, the actions of which result in the proliferation of arterial smooth muscle cells (SMC) - an essential feature of all atherosclerotic lesions. Grant funds are requested to support the continuation of tissue culture studies to further characterize PA as the principal platelet factor which not only triggers SMC proliferation, but also may stimulate the syntheses and secretion of collagen, proteoglycan, and lipid -integral components of the atherosclerotic lesion. Since hypoxia has been shown to elevate tissue PA levels, investigations are planned to evaluate the role of PA when SMC are exposed to a hypoxic environment -an effect which probably contributes to accelerated atherogenesis in smokers. The proposed examination of the effects of PA on the interaction between SMC and plasma lipoproteins and the binding, uptake, and degradation of 125I-LDL should provide useful insights into mechanism(s) of cholesterol accumulation in the atherosclerotic lesion.